A. Field of the Invention
This invention relates to medical imaging and specifically to a system and method for localization of certain types of abnormal tissue, such as malignant tissue, using radiography.
B. Description of the Related Art
Radiography involves examination of internal organs of the body by transillumination with X-rays. The image receptor may be radiographic film, a film/intensifying screen combination, a stimulable phosphor storage plate, a fluoroscopic image intensifier, an amorphous silicon sensor array, a CCD/scintillator combination, or another type of X-ray sensitive receptor. In digital radiography, a computer digitizes the acquired image and may enhance it using image processing algorithms. The most commonly performed radiographic procedures include mammography, in which images of the breast are generated to detect breast cancer, and thoracic radiography, in which images of the lungs and heart are generated to detect a variety of diseases, including lung cancer.
A major goal of radiography is the reliable detection of malignant tissue and its accurate differentiation from non-malignant tissue. In current practice, the radiologist decides whether tissue is malignant, benign or normal solely by visual inspection of the radiograph The appearance of tissue on a radiograph mainly depends on the degree to which the transilluminating X-ray beam is attenuated during its traversal of the different areas of the tissue being examined. However, it has been repeatedly demonstrated that the visual appearance of tissue on the radiograph is not a reliable criterion for definitive diagnosis of malignancy.
Studies confirm a high error rate in the radiological diagnosis of cancer. These errors fall into two categories: false positives and false negatives. A false positive, also called an error in specificity, occurs when a radiograph is judged to display malignant tissue that ultimately proves benign. A false negative, also called an error in sensitivity, occurs when malignant tissue actually present is not detected on the radiograph.
One of the most commonly performed radiographic procedures is mammography, in which the breasts are examined for evidence of cancer. Approximately 25 million primary screening mammograms are performed annually in the United States. However, the high incidence of false positives and false negatives reduces the reliability of mammography as a diagnostic tool.
The major sources of false positives on mammograms are cysts and fibroadenomas. Cysts are benign fluid-filled tissue structures that may often be present in an otherwise normal breast. Fibroadenomas are benign growths of tissue that may also be present in a normal breast. Both types of structures may feel lumpy during palpation by the patient or a physician, and may thus resemble malignant tumors in a physical examination. In addition, both cysts and fibroadenomas appear as areas of decreased radiographic density on mammograms. Their radiographic appearance can closely resemble that of malignant tumors, which also appear as areas of decreased density.
According to various published studies, between 6% and 13% of primary screening mammograms manifest radiographic evidence of possible malignancy, but of these positive or suspicious results, approximately 80% are ultimately diagnosed as benign [Elmore J G et al.: N. Eng. J. Med. 338: 1089-1096 (1998)]. However, as previously noted, it is currently impossible to reliably differentiate malignant from benign tissue solely by visual inspection of the mammogram. Consequently, the majority of patients with positive primary results require further diagnostic procedures, including additional mammograms and excisional (surgical) or needle biopsies. Secondary diagnostic workups that include biopsies usually cost between $1500-3000. In addition to increased cost, biopsies carry the risk of infection, scarring, pain, and anxiety.
Thus, a method for more accurate differentiation of malignant tissue from benign and normal tissue on mammograms would eliminate the need for many of the biopsies now performed, decreasing procedure cost and patient morbidity.
A more serious problem in diagnostic mammography is the high incidence of false negatives, in which malignant tumors that are actually present are not detected on the mammogram. Missed tumors may be detected months or years later on a subsequent mammogram or by palpation. During this interval the tumor may grow larger and, in the worst case, metastasize. Various published studies on diagnostic accuracy in mammography report a false negative rate of between 8% and 24% [van Dijck J A et al.: Cancer 72: 1933-1938 (1993); Bird R E et al.: Radiol. 184: 613-617 (1992); Wallis M G et al.: Clin. Radiol. 44: 13-15 (1991)]. Particularly in their early stages of development, malignant tumors may not be noticed even upon careful inspection of the mammogram by an experienced radiologist. Tumors may be too small to be detected, or their appearance may be obscured by benign tumors or cysts. The visibility of malignant tumors may be further obscured in younger women, whose breast tissue is often dense. As a consequence, the rate of false negatives in these women is even higher than in the general population.
It has reliably been demonstrated that the stage at which malignant breast tumors are detected is an important determinant of the effectiveness of therapy and of the patient's survival time. [Ries L A G et al. (eds): SEER Cancer Statistics Review, 1973-1995, National Cancer Institute (1998)].
The high incidence of missed cancers on mammograms suggests that there is a minimum size threshold for detection of malignant tumors using current radiographic methods, and that these tumors may be present in the body long before they are detected.
Thus, an improved method for visualization of small malignant tumors on mammograms would enable their earlier detection, enhance the effectiveness of therapy, and prolong patient survival time.
Similar diagnostic problems are common in thoracic radiography, in which radiographic imaging of the lungs and heart is performed to detect abnormal tissue, particularly malignant tumors. Over 16 million thoracic radiographs are performed annually in the United States. Approximately 3 of every 100 thoracic radiographs show evidence of small isolated masses in the lung. Approximately 50% of these masses, known as solitary pulmonary nodules, are benign. However, it is impossible to reliably differentiate malignant nodules from benign nodules solely by inspection of the radiograph. Definitive diagnosis of these nodules currently requires surgical resection or invasive biopsy. As in the case of breast biopsies, these procedures are expensive and add patient morbidity risk.
Thus, an improved method for differentiation of malignant tissue from benign and normal tissue on thoracic radiographs would reduce the large number of unnecessary follow-up procedures currently performed, decreasing cost and morbidity.
As in the case of mammography, false negatives in thoracic radiography lead to less effective therapy and shorter patient survival time. Particularly in their early stages of development, malignant lung tumors may not be detected even upon careful inspection of the radiograph. The early detection of lung cancer is of particular importance because the overall survival rate from the disease is very low. It has been repeatedly shown that the survival time of patients whose lung tumors are detected at an early stage in their development is much longer than that of patients whose tumors are detected in later stages [Ries L A G et al. (eds): SEER Cancer Statistics Review, 1973-1995, National Cancer Institute (1998)].
Thus, an improved method for visualization of small malignant lung tumors on thoracic radiographs would enable earlier detection of these tumors and prolong patient survival time.
Recognition of the current inadequacies of the radiographic art has led to attempts to develop more accurate methods for diagnostic imaging of cancer.
One commonly pursued approach to the improvement of diagnostic accuracy has been to increase the spatial resolution of radiographic imaging devices. Radiographs with higher spatial resolution improve the ability of the radiologist to visualize fine anatomical detail. However, this approach is fundamentally flawed because detection of malignant tissue, even in high-resolution images, still largely depends on variations in radiographic density. But, as previously noted, radiographic density alone is not a reliable criterion for detection of malignant tissue. Improved spatial resolution can therefore result in only a modest improvement in diagnostic accuracy.
A more successful approach to the improvement of diagnostic accuracy is based on generating images of tissue glucose metabolism using positron emission tomography (PET). These images, which measure physiological function, are referred to as functional images, in contrast to the anatomical images generated by most other commonly used imaging modalities. PET functional imaging exploits the fact that the glucose metabolic rate of malignant tissue is considerably elevated relative to that of benign and normal tissue in the same organ. In a PET scan, a positron-emitting radioactive glucose analog, typically .sup.18 F-2-fluoro-2-deoxyglucose, is administered to the patient. After an interval of approximately one hour, images of the distribution of the radioactive glucose analog in body tissue are acquired by a photon detector array that surrounds the patient. In direct comparisons with anatomical imaging modalities, including computed tomography, magnetic resonance imaging, and ultrasound, PET functional images of tissue glucose metabolism have repeatedly proven more sensitive and specific in the detection of malignant tumors, particularly those larger than 1 cm. [Hoh C K et al.: Semin. Nuc. Med. 27: 94-106 (1997); Conti P S et al.: Nuc. Med. Biol. 23: 717-735 (1996)]
The most formidable barrier to the use of PET is its cost. A cyclotron is required to generate the positron-emitting radiopharmaceuticals required in the imaging procedure, and a complex detector array is required to detect photon emission. Capital equipment costs of the imaging device and cyclotron are very high. In addition, radiochemists are needed to perform complex syntheses of radiopharmaceuticals whose half-lives are typically 2 hours. Because of the high capital equipment, materials, and labor costs, the cost of a PET scan to the patient is approximately $2500. Because of its prohibitive cost, PET imaging is not widely available, and is not likely to be used in the foreseeable future for routine cancer diagnosis.
A second disadvantage of PET is the lower spatial resolution of PET images compared to those generated by radiography. Relatively low spatial resolution is a limitation common to imaging modalities that depend on detector arrays for the measurement of high-energy particles emitted from radiopharmaceuticals. Because of its low spatial resolution, PET exhibits a high rate of false negatives in the detection of small malignant tumors.
A third disadvantage of PET is the length of the imaging procedure. The time required for a patient to be immobile during a PET scan may be one-half to one hour, while radiographic images can be acquired in a few minutes.
Another approach to the improved detection of malignant tissue has been the development of single-photon emission computed tomography (SPECT). In this imaging modality, a photon-emitting radiopharmaceutical is administered to the patient. After an interval during which the radioactive imaging agent accumulates in body tissue, images are acquired using a gamma camera. The gamma camera detects photons emitted by the imaging agent.
The most common radiopharmaceutical used in SPECT imaging of malignant tissue is Tc-99m-Sestamibi. Results of a number of studies have shown selective uptake of Tc-99m-Sestamibi in malignant tumors of various types.
Nevertheless, SPECT imaging has limitations that reduce its utility in the diagnosis of malignant tumors. In the diagnosis of breast cancer, a major limitation of the technique is the low spatial resolution of the images, which results in a sharp decrease in sensitivity for breast tumors smaller than 1.5 cm. By the time tumors have grown to this size, they are almost always palpable in physical examination by the patient or the physician, and may have advanced to a late stage in their development.
A second disadvantage of SPECT in breast cancer imaging is the relatively low specificity. In particular, Tc-99m-Sestamibi produces a significant number of false positives in patients with benign fibroadenomas. Since fibroadenomas constitute the most frequent source of false positives, and frequently result in unnecessary biopsies, the large number of false positives produced by Tc-99m-Sestamibi reduces its value in breast cancer imaging. In diagnostic imaging of the lung, SPECT generates false positives in conditions such as tuberculosis, pneumonia, and granulomas. It is thus inadequate for the reliable diagnosis of lung cancer.
Other imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound, are also used for diagnosis of malignant tumors, with varying degrees of success. However, over the past 15 years, clinical studies have repeatedly demonstrated that PET functional imaging of tissue glucose metabolism is the most accurate modality now available for the detection of malignant tissue.
A wide variety of contrast agents have also developed to enhance the delineation of tissue on radiographic images [Torsten et al.: U.S. Pat. No. 3,701,771; Speck et al.: U.S. Pat. No. 4,364,921; Nordal et al.: U.S. Pat. No. 4,250,113; Sovak et al.: U.S. Pat. No. 4,243,653]. However, almost all commonly used radiographic contrast agents function by passively outlining body organs and structures, thereby enhancing anatomical contrast on the radiograph. These imaging agents generally accumulate in the extracellular space. Commonly used radiographic contrast agents are hydrophilic, and are therefore not cell-membrane permeable [Speck U: Contrast Media pp. 1-23. Churchill Livingstone, New York (1988)]. Studies of tissue distribution at the cellular level confirm that commonly used radiographic contrast agents, such as metrizamide, iohexol, and meglumine calcium metrizoate, do not permeate the cell membrane nor enter the intracellular cytosol. [Golman K: Acta Radiol. Suppl. S335: 300-311 (1973); Ekholm S E et al.: Acta Radiol. [Diagn] (Stockh) 26: 331-336 (1985); Gjedde A: Acta Neurol. Scandinav. 66: 392-395 (1982); Kormano M, Frey H: Invest. Radiol. 15: 68-71 (1980)]. Because these contrast agents do not enter the cytosol, they do not specifically interact with intracellular targets, and therefore cannot be used to provide images which contain information on intracellular function or physiology. The utility of these radiographic contrast agents in the detection of functionally abnormal tissue is thereby limited.
Certain radiographic contrast agents have been developed which do enter and exit cells. However, in each instance, disadvantages associated with the mechanisms of cellular entry and exit of the molecules preclude their use in the diagnostic imaging applications addressed by the present invention.
Jung et al. (U.S. Pat. No. 5,141,739) disclosed a method of targeting X-ray contrast agents to a particular population of cells using a complex of a radio-opaque label and a polysaccharide. These contrast agents, whose major application is in the enhancement of CT images of the liver, enter cells through the mechanism of receptor-mediated endocytosis (RME). In this mode of delivery, contrast agent molecules attach to receptors on the cell surface and are internalized into the cell through pinching off of the cell membrane to form intracellular vesicles. Although these RME-based contrast agent molecules are physically localized within the cell, they are separated from the cytosol by the cell membrane surrounding the vesicle. Since the contrast agent molecules are not cell membrane-permeable, they cannot exit the vesicles which enclose them. They therefore have no direct access to the cytosol, and consequently do not specifically interact with, or bind to, intracellular targets. Similar contrast agents have been designed to enhance radiographic images of the liver by entering hepatocytes. As in the example cited above, molecules of these contrast agents are physically localized within the cell, but are compartmentalized within liposomes or intracellular vesicles. They are thus separated from the cytosol by the membrane barrier surrounding the liposome or vesicle. Since the molecules are not membrane-permeable, they do not have direct access to the cytosol and do not specifically interact with intracellular targets.
Ledley and Gersten (U.S. Pat. No. 4,716,225) disclosed a method of metabolic mapping of the central nervous system using iodinated sugar derivatives. The sugar derivatives are hexoses substituted with iodine atoms in either the C-2, C-5, or C-6 positions. Patterns of metabolism are mapped using CT scans to generate images of the concentration flux of the radio-opaque sugars in different areas of tissue in the central nervous system. The concentration flux is a measurement which reflects the rate of uptake of the compounds by cells.
The disclosed radio-opaque sugar derivatives are hydrophilic, and enter cells only via facilitated transport by the glucose transport (GLUT) proteins. Because the radio-opaque sugar derivatives are iodine-substituted in different ring positions, their interaction with the GLUT proteins differ from the interaction of native hexoses with these proteins. The binding requirements of the GLUT proteins are asymmetrical, and depend on which side of the cell membrane the sugar ligand is located. [Mueckler M: Eur. J. Biochem. 219: 713-725 (1994); Barnett J E G et al.: Biochem. J. 131: 211-221 (1973); Barnett J E G et al.: Biochem. J. 145: 417-429 (1975); Colville C A et al.: Biochem. J. 294: 753-760 (1993)]. Thus, it was reported that the disclosed molecules were able to enter cells, but once inside, were unable to freely exit. The compounds were shown to be present in tissue at higher concentrations 9 days after administration than 1 hour after administration. These figures indicate that the disclosed molecules had very slow rates of cellular uptake and elimination. The very slow rates of cellular entry and exit render these molecules of limited value in diagnostic imaging procedures. It is apparent that these molecules are not bidirectionally cell membrane permeable.
In addition, it has been demonstrated that the rate of glucose transport and expression of GLUT proteins in malignant tissue are not consistently abnormal relative to normal tissue. This inconsistency minimizes the utility of glucose transport as a diagnostic criterion for the detection of malignant tissue. [Nelson C A et al.: J. Nucl. Med 37: 1031-1037 (1996); Binder C et al.: Anticancer Res 17: 4299-4304 (1997)].
In order to improve the diagnostic utility of space-filling radiographic contrast agents, methods have been developed to enhance their visualization in the body. Mistretta et al. (U.S. Pat. No. 3,854,049; U.S. Pat. No. 3,974,386) described the use of multiple X-ray beams to enhance visualization of iodinated contrast agents in fluoroscopic imaging and to cancel the contribution of radiographic density of soft tissue and bone to the image. Another method isolated images of an iodinated contrast agent in the presence of tissue using spatial frequency encoding on a radiographic image [Macovski A et al.: Med. Phys 6: 53-58 (1979)]. These methods were directed solely to the visualization of extracellular, space-filling radiographic contrast agents. It was not suggested that cell membrane-permeable, intracellularly localized radiographic contrast agents might be imaged using these methods, as no such imaging agents were available or known at the time. In addition, these methods did not provide the capability of generating functional physiological images of body tissue, nor of presenting a visually aligned combination of a functional and an anatomical image of the same tissue.
A radiographic imaging agent that facilitated generation of functional physiological images in addition to the anatomical images now provided by radiographs, and which could be used with widely available radiographic imaging devices, would be of great value in the practice of radiography, particularly in the diagnostic imaging of cancer. This capability is not currently provided by any radiographic contrast agent.
In addition, the simultaneous display of functional images and anatomical images of high resolution, with both images superimposed in registration, is highly desirable for diagnostic and research purposes in medical imaging. Registration refers to the exact visual alignment, or superimposition, of two or more images from the user's viewpoint. Further, the capability of interactively varying the proportions of the displayed functional and anatomical information on a single image with complete registration would also be of great value. With this capability, for example, areas of abnormal functional (physiological) activity might be correlated with nearby anatomical landmarks, and either the anatomical or functional image might be emphasized. These capabilities would enhance the ability of the physician to precisely localize areas of abnormal tissue such as malignant tumors. These capabilities are not provided by any currently available single imaging modality.
Many approaches to the need for the simultaneous display and registration of functional and anatomical images have been developed [Woods et al.: J. Computer Assisted Tomogr. 22: 139-152 (1998); Alpert N M et al.: Neuroimage 3: 10-18 (1996); Friston et al.: Hum Brain Map. 2:165-189 (1995); Woods et al.: J. Comput. Assisted Tomogr. 17: 535-546 (1993)]. These methods of image display and registration all require the use of separate anatomical and functional imaging devices, such as PET and MRI, to sequentially acquire images of the patient during separate imaging procedures. The acquired image data arrays are later combined using software algorithms. These software computations are generally time-consuming and require considerable computational hardware.
Wang (U.S. Pat. No. 5,729,620) disclosed a system for superimposing digitized images representing X-ray data in registration with an annotation map. The annotation map may be constructed by a computer-aided diagnosis (CAD) system. The invention does not suggest a method of superimposing anatomical images in registration with functional (physiological) images of tissue, as CAD systems do not provide functional images.
It is thus evident that the present state of the diagnostic imaging art does not provide a sufficiently accurate, inexpensive, and widely available modality for detection and localization of certain types of tissue such as malignant tissue. An ideal imaging modality should combine the proven diagnostic accuracy of functional imaging of tissue physiology with the high anatomical resolution of radiography. It may also provide the ability to display functional and anatomical information on a single image with complete registration. An imaging modality with these characteristics should improve detection of small tumors at an earlier stage in their development, and improve differentiation of malignant from non-malignant tissue. Both false negative and false positive errors should thereby be reduced. The diagnostic imaging of other types of abnormal tissue should also be improved. The ideal imaging modality should also provide low-cost images, improve the accuracy of currently installed radiographic imaging devices, and not require the use of radiopharmaceuticals. An imaging modality providing these advantages should satisfy an urgent need in the practice of diagnostic imaging.